The hematological effects of acute, high dose total body irradiation (TBI) can lead to death without supportive care, such as hematopoietic transplant, transfusions and other supportive care measures. However, such supportive measures cannot be readily administered to a potentially large number of victims of high dose radiation exposure following a nuclear accident or direct acts of terrorism. If such disasters were to occur, military personnel and civilians alike would be left in great jeopardy. One of the deleterious effects of high dose radiation is the induction of a hematopoietic syndrome. To counteract the potentially lethal effects of hematopoietic syndrome, effective remedial drugs that can be quickly distributed shortly after the radiation incident are in great need.
Currently, there are no available drugs that are effective in increasing survival and regenerating hematopoiesis. Moreover, in the face of a radiation-related disaster or act of terrorism, the immediate distribution of such effective drugs to military personnel or civilians, if these were to be available, would not be practically possible. It is anticipated that a lag time of at least several hours, and perhaps 24 hours or longer, would be necessary to distribute such drugs to the scene of such a radiation disaster or act of terrorism. Thus, it is critically important that effective drugs that can be used to increase survival and regenerate hematopoiesis exhibit efficacy at protracted time intervals following acute exposure to ionizing radiation.
Several studies performed in the mid 80's suggested that proinflammatory cytokines could confer radioprotection when administered prior to lethal doses of radiation (Neta R. et al., Lymphokine Res. 1986;5 Suppl 1:S105-10; Neta R. et al., J Immunol. 1986 April 1;136(7):2483-5; Schwartz G. N. et al., Immunopharmacol Immunotoxicol. 1987;9(2-3):371-89). However, it was recognized by several later studies that the use of IL-12 for prophylactic and therapeutic treatments of lethal irradiation suffered from significant drawbacks. One such adverse effect was that IL-12 administered at a high dose of 1000 ng per mouse radiosensitized, rather than radioprotected, the gastrointestinal tract, resulting in lethal gastrointestinal syndrome in irradiated mice (Neta R. et al., J Immunol. 1994 November 1;153(9):4230-7). This work led to the conclusion that IL-12 sensitized the intestinal tract at levels necessary for protection of bone marrow cells (Neta R., Environ Health Perspect. 1997 December;105 Suppl 6:1463-5).
Consistent with these findings, Hixon et al. (Hixon et al., Biol Blood Marrow Transplant. 2002;8(6):316-25) showed that repeated administration of 500 ng IL-12 to BALBc mice who received bone marrow transplants following lethal whole body irradiation, resulted in acute lethal toxicity within 4 to 6 days. In contrast, Hixon et al. demonstrate that under identical conditions, BALBc mice that did not receive IL-12 administration recovered 100% of the time.
In the event of a nuclear event, whether accidental or malicious, pre-administration of drugs that promote survival is simply not possible. For example, in the event of a nuclear disaster, where large numbers of people and animals may require therapeutic administration, sufficient time will be required for the large-scale distribution of radiation treatments. Methods are needed for treatment that are effective when administered at protracted times following acute exposure to whole body ionizing radiation.
As such, there remains a need in the art for drugs that are effective in increasing survival and regenerating hematopoiesis when administrated at protracted times following acute exposure to whole body ionizing radiation. The present invention satisfies these and other needs by providing methods of treating a subject following an acute exposure to non-therapeutic whole body ionizing radiation via administration of IL-12 at protracted timepoints.